A stewardship intervention program for safe medication management and use of antidiabetic drugs

Figures & data

Table 1 Key indicators of the diabetes specialist nursing service

Indicators	2011	2012	2013
Number of times specialist nurses visited diabetes inpatients	6,238	6,075	5,702
Number of times specialist nurse visited diabetes inpatients with hypoglycemia	310	351	408
Number of diabetes specialist nursing consultations for inpatients	107	152	118
Number of special education and counselling in diabetes nurse clinics (Diabetes Center)	422	660	500
Number of diabetes patients participating in monthly held educational classes on self-management of diabetes	598	712	517

Figure 1 Quality improvement in the storage of insulin that is currently in use.

Notes: (A) Before: All patients’ insulins were stored in a basket. (B) After: Each patient’s insulins were stored in a separate compartment.

Table 2 Auditing pharmacists’ focus on clinically relevant drug interactions related with oral antidiabetic drugs

Class	Coadministered medications	Potential consequence, clinical relevance, and risk management
Sulfonylurea	CYP2C9 inhibitors (voriconazole, fluconazole, sulfamethoxazole, fluvastatin, fluvoxamine) CYP2C9 inducers (rifampicin, ritonavir, nelfinavir, St John’s wort)	Concomitant use of a CYP2C9 inhibitor may result in exaggerated pharmacodynamic effects of sulfonylureas and increases the risk of hypoglycemia. The minimum fasting plasma glucose values are more often below the target range in patients with potential interactions.^Citation14^–^Citation16 Physicians should consider the alternatives of CYP2C9 inhibitors (eg, non-CYP2C9-metabolized statins, such as atorvastatin instead of fluvastatin) or reduce the dose of sulfonylurea The apparent clearance of sulfonylurea may potentially increase. People with diabetes receiving such combination should be closely monitored to evaluate possible signs of reduced efficacy. Physicians should consider the alternative hypoglycemic drug or increase the dose of sulfonylurea^Citation17^–^Citation19
Metformin	Contrast agent	Contrast agent can greatly increase metformin concentration in the blood, resulting in higher risk of lactic acidosis and acute renal failure.^Citation20 Serum creatinine should be measured before contrast-enhanced examination for patients taking metformin. Those with normal renal function should stop taking metformin at the time of contrast administration and should restart the drug no sooner than 48 hours after contrast administration. Those with renal dysfunction should stop using metformin 48 hours before intravenous contrast and restart the drug no sooner than 48 hours after contrast administration and only if renal function remains stable
Meglitinide analogs
Nateglinide	Fluconazole	Concomitant use of fluconazole with nateglinide may prolong its blood glucose-lowering effect because fluconazole can raise the plasma concentrations and reduce the systemic elimination of nateglinide by CYP2C9 inhibition.^Citation21 Repaglinide is an alternative to nateglinide when fluconazole is coprescribed
Repaglinide	Clarithromycin	Even low doses of clarithromycin can increase the plasma concentrations and effects of repaglinide, due to CYP3A4 inhibition. The risk of hypoglycemia may increase when the two drugs are comedicated.^Citation22 Reduction in repaglinide dosage may be necessary. Physicians may also consider an alternative antibiotic (eg, azithromycin)
	Cyclosporine	AUC and Cmax of repaglinide will be markedly raised due to CYP3A4 and OATP1B1 inhibition by cyclosporine, resulting in increased risk of hypoglycemia.^Citation23 Nateglinide is an alternative to repaglinide when cyclosporine is coprescribed
	Gemfibrozil	AUC and Cmax of repaglinide will significantly increase due to CYP2C8 and OATP1B1 inhibition by gemfibrozil. Hypoglycemic effects may be potentially augmented.^Citation24 Bezafibrate and fenofibrate are alternatives to gemfibrozil when repaglinide is coadministered.^Citation25 Meanwhile, nateglinide is an alternative to repaglinide when gemfibrozil is coprescribed^Citation26
Thiazolidinediones
Pioglitazone	Gemfibrozil	AUC of pioglitazone will significantly increase due to CYP2C8 inhibition by gemfibrozil, especially in CYP2C8*3 carriers.^Citation27 Hypoglycemic effects may be potentially augmented when gemifibrozil is coprescribed
DPP-4 inhibitors
Saxagliptin	CYP3A4 inhibitors (HIV-protease inhibitors, itraconazole, ketoconazole, clarithromycin)	Elevated plasma drug concentrations are expected, glucose monitoring is recommended, and dosage adjustments may be required^Citation13

Abbreviations: AUC, area under the concentration curve; C_max, maximum concentration of drug in the blood.

Figure 2 Look-alike/sound-alike insulin analogs.

Notes: (A) NovoMix 30^® (biphasic insulin aspart). (B) NovoRapid^® (insulin aspart). (C) NovoMIx 30^® (biphasic insulin aspart) with an additional label. (D) Humalog Mix^® 75/25 (75% insulin lispro protamine suspension with 25% insulin lispro injection) with an additional label. (E) Humalog^® (insulin lispro).

Figure 3 Number of MAEs related to insulin during 2011–2014.

Abbreviation: MAEs, medication administration errors.

Figure 4 Subtype distribution of medication administration errors related to insulin during 2011–2014.

Table 3 Comparison of insulin injection technique in SAHZU program with data from other surveys

Items	SAHZU October 2012 (n=160)	2008–2009 questionnaire survey in 16 countries (n=4,352)	Survey in patients with type 2 diabetes in mainland PR China in 2010 (n=380)
Check injection sites prior to injection	85.6%	36%	76.8%
Rotation of injecting sites	98.1%	91%	16.0%
Priming before injection	98.1%	No data	72.1%
Remix before use	94.5%	65%	76.8%
Keep the pen needle under the skin for >10 seconds	99.4%	23.5%	74.2%
Using the pen needle only once	88.7%	43.4%	8.7%

Notes: Data from De Coninck et al³⁰ and Ji et al.³¹

Abbreviations: PR China, People’s Republic of China; SAHZU, Second Affiliated Hospital of Zhejiang University.

Table 4 Occurrence rates of hypoglycemia in hospitalized diabetes patients who were not from Department of Endocrinology during 2010–2013

Year	Number of diabetes patients	Number of diabetes patients with hypoglycemia	Occurrence rate
2010	5,309	439	8.27%
2011	6,315	339	5.37%*
2012	6,974	351	5.03%*
2013	7,375	408	5.53%*

Notes:

* P<0.01 versus data in 2010 (chi-square test).

Figure 5 Occurrence rate of hypoglycemia in diabetes inpatients in neurology wards during 2010–2013.

Notes: *P<0.01 (data during 2011–2013 versus data in 2010).

Figure 6 Quality improvement in the percentage of correctly managed hypoglycemia events in 2014.

Table S1 Inappropriate medication use in diabetes patients during on-site inspection in the first and second quarter of 2014

Inspection time	Problems	Action
January–March	• Inappropriate choice of insulin (n=2)
	1. The patient received NovoRapid^® (insulin aspart) 12 units before breakfast and 10 units before supper	NovoRapid^® was replaced by NovoMix 30^® (biphasic insulin aspart) twice daily
	2. The patient received Novolin^® 30R (isophane protamine biosynthetic human insulin injection [premixed 30R]) 13 units before breakfast, and 3 units before supper. Due to hyperglycemia, Lantus^® (insulin glargine) 10 units QN was nearly added	Physician was advised to replace Novolin 30R by NovoRapid^®. Glycosylated hemoglobin was checked, and endocrinology consultation was requested
	• Inappropriate drug combination (n=1)
	1. The patient received Humulin R^® (regular human insulin injection) three times daily plus Lantus^® QN during the stay in hospital. Physician order at discharge was NovoMix 30^® twice daily plus Lantus^® QN	Physician order of Lantus^® QN at discharge was canceled. NovoMix^® 30 twice daily was prescribed, and referral to the Department of Endocrinology was required 1 week later
	• Inappropriate dosing frequency (n=3)
	1. The patient received NovoMix 30^® 16 units before breakfast, 13 units before lunch, and 16 units before supper. Several hypoglycemia events occurred after admission	NovoMix^® 30 dose at lunch was canceled, and doses in morning and evening were adjusted
	2. The patient received Glucotrol XL^® (glipizide extended release) 5 mg, three times daily	Once daily use of Glucotrol XL^® was suggested, and endocrinology physician was consulted
	3. The patient received Humulin^® 30/70 (70% human insulin isophane suspension and 30% human insulin injection) 6 units before breakfast, 8 units before lunch, and 10 units before supper, plus Lantus^® 10 units QN after admission. Later, the regimen was switched to Humalog^® 25 (75% insulin lispro protamine suspension and 25% insulin lispro injection) three times daily plus Lantus^® QN. The patient had been just discharged before the arrival of on-site inspector	The diabetes nurse contacted the patient family and requested patient to see local endocrinology physician
	• Inappropriate dosing route (n=1)
	1. The patient was given nasogastric liquid diet and glipizide sustained release capsule 5 mg, which should not be opened and administered via nasogastric tube	The inappropriate physician order was identified 1 day after admission Glipizide sustained release was canceled
	• Poor awareness of medication reconciliation (n=7)
	1. The patient received Humulin^® 30/70 12 units before three meals plus Novolin^® N (isophane protamine biosynthetic human insulin injection) 4 units QN. He would receive surgery the next day	Physician was advised to stop insulin the same day and prescribe insulin when postoperative diet recovered. Postoperative follow-up indicated use of NovoRapid^® plus Lantus^®
	2. Repaglinide 1 mg three times daily plus Lantus^® QN still resulted in high blood sugar. The regimen was replaced by Humulin^® R three times daily; however, the physician forgot to stop repaglinide use	Repaglinide use was canceled
	3. Repaglinide 1mg three times daily plus Lantus^® QN still resulted in high blood sugar. The regimen was replaced by NovoRapid^® three times daily; however, the physician forgot to stop repaglinide use	The inappropriate physician order was identified 1 day after admission; repaglinide was canceled thereafter
	4. The patient received Diamicron^® MR (gliclazide modified release tablets) 30 mg once daily, then the hypoglycemic regimen was switched to Humulin^® R three times daily plus Lantus QN during the stay in hospital; however, the physician forgot to stop Diamicron^® MR use	The diabetes nurse contacted the physician. However, when discharged the patient was still receiving Diamicron^® MR 30 mg once daily, NovoRapid^® three times daily and Lantus QN
	5. Diamicron^® MR 60 mg once daily was initially used. Later, the hypoglycemic regimen was switched to Humulin^® R three times daily plus Lantus^® QN; however, the physician forgot to stop Diamicron^® MR use. A hypoglycemic event occurred at bedtime	The physician was advised to stop Diamicron^® use
	6. The patient received NovoMix 30^® 16 units before breakfast, 8 units before supper plus Lantus^® 10 units QN. This regimen was the same with that before admission and was used for 5 days after admission	Physician was advised to switch to NovoRapid^® three times daily plus Lantus^® QN
April–June	• Inappropriate choice of insulin (n=4)
	1. The patient received Humalog^® 25 16 units before breakfast, 8 units before supper plus Lantus^® 8 units QN	Diabetes nurse suggested physician ask for consultation
	2. The patient received NovoMix 30^® 6 units before breakfast, 8 units before lunch, 8 units before supper plus Lantus^® 6 units QN	NovoMix 30^® was replaced by NovoRapid^®
	3. The patient received NovoMix 30^® 14 units before breakfast, 14 units before supper plus Lantus^® 24 units QN. The regimen patient had received before admission did not change after hospitalization. The inappropriateness was found the day after admission	Diabetes nurse suggested physician ask for consultation. After surgery, the regimen was replaced by NovoRapid^® three times daily plus Lantus^® QN
	4. The patient received NovoMix 30^® 8 units before breakfast, 8 units before lunch, 8 units before supper plus Lantus^® 10 units QN	The physician order was canceled, and the patient was transferred to the Department of Endocrinology

Abbreviation: QN, Quaque nocte, every night.

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